QSAR modeling and design of cationic antimicrobial peptides based on structural properties of amino acids.
Novispirin G10 is an alpha-helical antimicrobial peptide designed in an effort to develop alternative treatments against multidrug-resistant micro-organisms. To further optimize the antimicrobial activity, 58 novispirin analogs were constructed and used to establish a quantitative structure-activity relationship model. A statistically significant model (r2 = 0.73, q2 = 0.61) was obtained using a set of 69 selected molecular descriptors. Among these, VolSurf and charged partial surface area descriptors played a dominant role. Analysis of the model indicated that hydrophobicity, amphipathicity and charge were the most important features influencing activity for this set of peptides. Furthermore, the ability of the quantitative structure-activity relationship model to predict bioactivity was evaluated by analyzing a set of 400 novispirin analogs designed by molecular modeling. Out of these 400, 16 new novispirins with a higher predicted antimicrobial activity were tested in the suicide expression system, and about three out of four appeared more potent than the parent novispirin G10. Combination of VolSurf and charged partial surface area descriptors seems relevant to depict the interaction between novispirin and its target(s), presumably the microbial cell membrane. The presented findings show that modeling and quantitative structure-activity relationship methods can be useful in the construction of and/or optimization of the bioactivity of antimicrobial peptides for further development as effective antibiotic therapeutics.